title: Benzochalcones bearing pyrazoline moieties show anti-colorectal cancer activities and selective inhibitory effects on aurora kinases.
abstract: Colorectal cancer is the third and fourth leading cause of cancer in males and females, respectively. Flavonoids, including chalcones, are secondary metabolites in plants that exhibit diverse biological activities, including antibacterial, antimalarial, and antitumor activities. In order to find potent and novel chemotherapy drugs for colorectal cancer, a series of benzochalcone derivatives, in which an α,β-unsaturated carbonyl group was replaced with a pyrazoline, was designed and synthesized. A clonogenic survival assay was performed with each derivative to evaluate antitumor activity. 1-(5-(2,4-Dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol (derivative 7) had the most potent inhibitory effect on the long-term clonogenicity of HCT116 human colorectal cancer cells (IC50=2.4 μM). The results of Western blot and flow cytometric analyses suggested that derivative 7 could inhibit the proliferation of colorectal cancer cells through inhibition of cell cycle progression and induction of apoptosis. To elucidate its molecular mechanism, in vitro kinase binding assays were carried out, which demonstrated that derivative 7 inhibited aurora kinases A and B selectively. The binding modes between the compound and aurora kinases were interpreted using in silico docking experiments to explain the selective inhibitory effects on aurora kinases A and B. These findings will facilitate the design of potent novel benzochalcones as anticancer agents.
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Hyuk
authors.initials: H
authors.lastname: Yoon
authors.forename: Doseok
authors.initials: D
authors.lastname: Hwang
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Ahn
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Koh
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D064127:Aurora Kinases
keywords: Aurora kinase; Benzochalcone; Clonogenicity; Colorectal cancer; Flavonoid; In silico docking